Contactdependent Help Mediated By Cd40cd40l Interaction

Formation of a T-B conjugate not only leads to the directional release of TH-cell cytokines, but also to the up-regulation of

CD40L (CD154), a TH-cell membrane protein that then interacts with CD40 on B cells to provide an essential signal for T-cell-dependent B-cell activation. CD40 belongs to the tumor necrosis factor (TNF) family of cell-surface proteins and soluble cytokines that regulate cell proliferation and programmed cell death by apoptosis. CD40L belongs to the TNF receptor (TNFR) family. Interaction of CD40L with CD40 on the B cell delivers a signal (signal 2) to the B cell that, in concert with the signal generated by mIg crosslinkage (signal 1), drives the B cell into G1 (see Figure 11-10c). The signals from CD40 are transduced by a number of intracellular signaling pathways, ultimately resulting in changes in gene expression. Stud ies have shown that although CD40 does not have kinase activity, its crosslinking is followed by the activation of protein tyrosine kinases such as Lyn and Syk. Crosslinking of CD40 also results in the activation of phospholipase C and the subsequent generation of the second messengers IP3 and DAG, and the activation of a number of transcription factors. Ligation of CD40 also results in its association with members of the TNFR-associated factor (TRAF) family. A consequence of this interaction is the activation of the transcription factor NF-6B.

Several lines of evidence have identified the CD40/CD40L interaction as the mediator of contact-dependent help. The role of an inducible TH-cell membrane protein in B-cell activation was first revealed by experiments in which naive B cells were incubated with antigen and plasma membranes prepared from either activated or resting TH-cell clones. Only the membranes from the activated TH cells induced B-cell proliferation, suggesting that one or more molecules expressed on the membrane of an activated TH cell engage receptors on the B cell to provide contact-dependent help. Furthermore, when antigen-stimulated B cells are treated with anti-CD40 monoclonal antibodies in the absence of TH cells, they become activated and proliferate. Thus, engagement of CD40, whether by antibodies to CD40 or by CD40L, is critical in providing signal 2 to the B cell. If appropriate cy-tokines are also added to this experimental system, then the proliferating B cells will differentiate into plasma cells. Conversely, antibodies to CD40L have been shown to block B-cell activation by blocking the CD40/CD40L interaction.

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